Synthesis method and intermediates of pyridin-2-yl-methylamine

ABSTRACT

The invention concerns a novel method for preparing pyridin-2-yl-methylamine derivatives by reducing amination of cyanohydrins.

The present invention relates to a novel method for preparingpyridin-2-yl-methylamine derivatives of formula (I):

in which:

-   u represents a hydrogen atom or a methyl radical;-   v represents a hydrogen atom or a chlorine atom or a methyl radical;-   w represents a hydrogen atom or a fluorine atom or a methyl radical;-   y represents a chlorine atom or a methyl radical;-   z represents a hydrogen atom or a fluorine atom or a chlorine atom    or a methyl radical; and-   A represents:    -   a hydrogen atom or a fluorine atom or a chlorine atom;    -   a C₁–C₅ alkyl radical;    -   a fluoroalkyl radical;    -   a cyclopropyl radical;    -   a 5-membered aromatic heterocyclic group;    -   an alkoxy or alkylthio group;    -   a cyclic amino group;    -   an alkoxycarbonyl group; or    -   an amino group of the type:

-    in which R2 or R3, which are identical or different, represent    hydrogen, or a C₁–C₅ alkyl radical as defined above or a cyclopropyl    or cyclobutyl radical or a trifluoromethyl radical.

The method is characterized by the reaction of a cyanohydrin of formula(III):

and of a pyridin-2-yl-methylamine of formula (IV):

According to a particular embodiment of the invention, the reactionmedium may, in some cases, be advantageously made basic by the additionof an organic base of the tertiary amine type.1,4-Diaza-bicyclo[2.2.2]octane will be used in particular.

According to another characteristic embodiment of the method of theinvention, the reaction medium is made reducing by the addition of asimple or complex boron hydride, in particular sodium cyanoborohydride.

According to an additional characteristic of the present invention, sucha method will be advantageously carried out in a reaction medium of thealcohol type, in particular in a methanolic medium.

According to another additional characteristic of the method of theinvention, the primary amine, a starting reagent of formula (IV), may beused in the form of a hydrochloride, this being more particularly so inthe case of the preparation of a pyridin-2-yl-methylamine.

These compounds are useful as medicaments, in particular asantidepressants and analgesics.

In the prior art, illustrated in WO 9822459, the compounds of formula(I) are obtained from a 1-benzoyl-piperidin-4-one (formula II). Theketone functional group of the compounds of formula (II) is converted toan epoxide (IIa), which, when treated with an excess of the hydrogenfluoride-pyridine complex, leads to a1-benzoyl-4-fluoro-4-hydroxymethylpiperidine (IIb). The primary alcoholfunctional group of this compound (IIb) is then activated in the form ofan ester of para-toluenesulfonic acid (IIc) to give, after reaction withpotassium phthalimide, a1-benzoyl-4-fluoro-4-(1-phthalimidoylmethyl)piperidine (IId). Thisinter-mediate, after treating with ethanolamine, gives a1-benzoyl-4-fluoro-4-aminomethylpiperidine (IIe), which is then used ina reductive amination reaction with an appropriate aldehyde to give thecompounds of formula (I).

The production of compounds of formula (I) according to the method, asdescribed in WO 9822459, requires 6 steps starting with the intermediateof formula (II) and gives a mean optimized overall yield of 5%.

The present method, which uses a new reductive amination reactionbetween a cyanohydrin (formula III) and a pyridin-2-yl-methylamine(formula IV), advantageously replaces the previous method.

The method using this novel reaction is described in scheme II:

A Darzens reaction between benzoylpiperidin-4-ones (II) and anacetonitrile halide (A. Jonczyk, Tetrahedron Lett. (1972), 23, 2395–96)gives the corresponding cyanoepoxides (formula V). This reaction isadvantageously carried out according to a phase transfer technique underthe operating conditions developed by the inventors. The opening of theepoxide (V) by means of hydrofluoric acid or other fluorinating agents,according to the techniques described for example in:

-   J. Fluorine Chem. (1999), 99(2), 95–97-   Yuki Gosei Kagaku Kyokaishi (1998), 56(4), 312–319-   J. Fluorine Chem. (1995), 70(1), 1–3-   J. Fluorine Chem. (1995), 70(1), 141–4-   Tetrahedron Lett. (1990), 31(49), 7209–12-   J. Chem. Soc., Chem. Commun. (1989), (23), 1848–50 gives the    cyanohydrins of formula (III). The latter are then reacted with the    pyridin-2-yl-methylamines (formula IV) or their salt, in a reducing    and optionally basic medium in order to directly give the compounds    of formula (I). The average overall yield of this method, starting    with the intermediate of formula (II) is 23%, which represents a    gain in productivity of 450% compared with the initial method    (scheme I).

The yields of this new reaction, applied to the cyanohydrin (III),(scheme II), and the primary amine (IV), and the purity of the productsobtained, therefore allow a more economical and effective industrialsynthesis.

The reductive amination reaction is advantageously carried out at roomtemperature.

When the pyridin-2-yl-methylamines are in salt form, then the reactionmedium is advantageously made basic by means of an organic base, of thetertiary amine type, such as for example 1,4-diazabicyclo[2.2.2]octane(DABCO).

The reducing medium is advantageously obtained by means of a simple orcomplex boron hydride, or a mixture of boron hydrides, and in particularsodium cyanoborohydride (NaBH₃CN).

In some cases, in particular when(6-aminomethyl-5-methyl-pyridin-2-yl)methylamine (formula IVb) is used,a by-product of formula (VII) appears, (scheme III).

This side reaction can be eliminated by adding iron sulfate (FeSO₄.7H₂O)to the reaction medium. Other metal salts capable of completing thecyanide ions can also be used in the reductive amination reaction inquestion.

The preparation of the (5-methyl-pyridin-2-yl)methylamine (formula IVa)used in this method is described in EP 718 300 or U.S. Pat. No.4,482,437.

The preparation of (6-aminomethyl-5-methylpyridin-2-yl)methylamine(formula IVb), is described below and was carried out according to thesequence of reactions represented in scheme IV.

The preparation of 2-ethoxycarbonyl-5-methyl-6-chlorpyridine (compoundIX) is described in WO 9822459. This intermediate, when treated withaqueous ammonia, gives the 2-carboxamido-5-methyl-6-chloropyridinederivative (formula X) which reacts in the hot state and under pressurewith methylamine in the presence of copper sulfate to give2-N-methylamido-5-methyl-6-methylaminopyridine (formula XI). Acidhydrolysis of the amide, followed by esterification and treatment withaqueous ammonia gives 2-carboxamido-5-methyl-6-methylaminopyridine(formula XIII) which is reduced to(6-aminomethyl-5-methylpyridin-2-yl)methylamine (formula IVb) by meansof lithium aluminum hydride.

The following examples illustrate the invention without however limitingthe scope thereof.

EXAMPLE 1 (6-Aminomethyl-5-methylpyridin-2-yl)-methylamine (IVb)

Step 1: 2-Carboxamido-5-methyl-6-chloropyridine (IX).

Dissolve 26 g of 2-ethoxycarbonyl-5-methyl-6-chloropyridine (crude oilcontaining about 60% of ester) in 130 ml of methanol. Add 200 ml of 32%aqueous ammonia and stir overnight at room temperature. The product isrecovered by filtration and gives, after washing with water and dryingunder vacuum, 13 g of white crystals. m.p.=146° C.

Step 2: 2-Methylcarboxamido-5-methyl-6-methylamino-pyridine (XI).

73 g of 2-carboxamide-5-methyl-6-chloropyridine and 200 ml ofmethylamine at 40% in ethanol, 110 ml of methylamine at 40% in water and34 g of anhydrous copper sulfate are introduced into a sealed stainlesssteel reactor. The reactor is then closed and heated, with stirring, for24 hours at 110° C. After cooling, the reaction medium is diluted with300 ml of water and aqueous ammonia at 32%. The product is extractedtwice with dichloromethane and then washed with salt water. After dryingand evaporation, 52.4 g of white crystals are recovered. m.p.=158° C.

Step 3: 5-Methyl-6-methylaminopyridine-2-carboxylic acid (XII).

52 g of 2-methylamino-5-methyl-6-methylaminopyridine are added to asolution of 410 ml of 95% sulfuric acid in 100 ml of water and thenmixture is heated for 48 hours at 100° C. After cooling, the reactionmedium is poured over ice and neutralized with aqueous ammonia. Thewater is evaporated under vacuum and the residue is taken up inmethanol. After filtration of the minerals, evaporation of the methanolprovides 57 g of a brown solid mass which will be used in the next stepwithout further purification.

Step 4: 2-Carboxamido-5-methyl-6-methylaminopyridine (XIII).

50 g of the solid obtained above are taken up in 1.5 l of ethanolsupplemented with 38 ml of concentrated sulfuric acid. The mixture isheated at the reflux temperature of the solvent for 24 hours. Aftercooling, 1 liter of 32% aqueous ammonia is added and the mixture isheated for 4 hours at 50° C. The ethanol is evaporated and the residuesupplemented with 100 ml of salt water is extracted 10 times withdichloromethane and then the organic phases are washed with N sodiumhydroxide, dried over MgSO₄ and evaporated to dryness. The crystals arewashed with ether and then dried to give 20.5 g of white crystals.m.p.=182° C.

Step 5: (6-Aminomethyl-5-methylpyridin-2-yl)methylamine (IVb)

11.9 g of 2-carboxamido-5-methyl-6-methylaminopyridine are dissolved in60 ml of tetrahydrofuran. 143 ml of a 1 M lithium aluminum hydridesolution in tetrahydrofuran are then slowly introduced. The solution isheated at the reflux temperature of the solvent for 4 hours, and thencooled on an ice bath. 5 ml of water are then introduced dropwise,followed by 3.75 ml of 20% sodium hydroxide and finally 35 ml of water.The white solid is separated by filtration and the organic phase isevaporated to dryness. The residue is chromatographed on silica 60 witha dichloromethane 90-methanol 9-aqueous ammonia 1 mixture to give 8.4 gof a yellow oil.

¹H NMR (DMSO-d₆): δ 7.12 (d, J=7.16 Hz, 1H)-6.42 (d, J=7.16 Hz, 1H)-5.80(m, 1H)-3.62 (s, 2H)-2.82 (d, J=4.8 Hz, 3H)-1.99 (s, 3H)-1.5-2.1 (broad,2H).

EXAMPLE 2[1-(3-Chloro-4-fluorobenzoyl)-4-fluoro-piperidin-4-yl]hydroxyacetonitrile(III)

Step 1:6-(3-Chloro-4-fluorobenzoyl)-1-oxa-6-azaspiro[2.5]octane-2-carbonitrile(V).

A suspension of 1-(3-chloro-4-fluorobenzoyl)piperidin-4-one (4160 g,16.27 mol) in 28.4 liters of dichloromethane and 11.7 liters of sodiumhydroxide at 30.5%, supplemented with 186 g of tetrabutylammoniumchloride, is cooled to 15° C. Chloroacetonitrile (1540 ml, 24.4 mol) isthen added slowly and with vigorous stirring and the mixture is stirredfor 3 hours at 20° C. Further addition of chloroacetonitrile (500 ml) iscarried out in order to complete the reaction. The reaction medium isdiluted with dichloromethane (8.5 liters) and water (20 liters) and thenseparated by decantation and washed again with water. The brown solutionobtained is decolorized with 2 kg of silica and 500 g of animal charcoaland then evaporated to dryness. The residue obtained is crystallizedfrom isopropanol in order to give, after filtration, 3426 g of browncrystals. m.p.=100–101° C.

Step 2:[1-(3-Chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl]hydroxyacetonitrile(III).

6-(3-Chloro-4-fluorobenzoyl)-1-oxa-6-azaspiro[2.5]-octane-2-carbonitrile(2620 g, 8.89 mol) dissolved in dichloromethane (6.6 liters) isintroduced into a hastelloy reactor equipped with an appropriate gaswasher (HF vapors). The solution is brought to 15° C. and 2.91 kg of theHF/pyridine complex at 70% are added and the medium is stirred for 6hours at 40° C. The reaction medium is then washed twice with 10 litersof water and then with a K₂CO₃ solution and finally with water. Theorganic phase is evaporated under vacuum and the residue crystallizedfrom 10 liters of isopropanol. The filtration and drying under vacuum ofthe precipitate provide 1540 g of white crystals. m.p.=139–140° C.

EXAMPLE 3(3-Chloro-4-fluorophenyl)(4-fluoro-4-{[(5-methylpyridin-2-ylmethyl)amino]methyl}piperidin-1-yl)-methanone(Ia)

Introduce the[1-3-chloro-4-fluorobenzoyl)-4-piperidin-4-yl]hydroxyacetonitrile (5.3g, 0.0169 mol), (5-methylpyridin-2-yl)methylamine (dihydrochloride) (3.6g, 0.0185 mol), 1,4-diazabicyclo[2.2.2]octane (6.2 g, 0.055 mol), sodiumcyanoborohydride (1.25 g, 0.02 mol) and 150 ml of methanol into around-bottomed flask. The whole is stirred for 4 hours at roomtemperature, and then evaporated to dryness. The residue is taken up insodium bicarbonate and extracted with ethyl acetate, the organic phasesare washed with water and then dried over MgSO₄ and evaporated. Theresidue is chromatographed on silica 60 with a dichloromethane95-methanol 4.5-aqueous ammonia 0.5 mixture to give 5.22 g of oil (78%).This oil is then treated in ethyl acetate with one equivalent of fumaricacid to give the white crystalline salt. m.p.=157° C.

MS: DCI>0 MH⁺m/z=394. Elemental analysis: calculated: C, 56.53%, H5.14%; N, 8.24%. found: C, 56.67%; H, 5.21%; N, 8.41%. ¹H NMR (DMSOd₆):δ 10.4-9.4 (broad, 3H)-8.4 (dd, ⁴J=1.40 Hz-⁵J=0.83 Hz, 1H)-7.7 (dd,⁴J=7.18 Hz-⁴J=1.93 Hz, 1H)-7.6 (dd, ³J=8 Hz, ⁴J=1.5 Hz, 1H)-7.50 (dd³J=8.6 Hz, ³J=8.6 Hz, 1H)-7.45 (ddd, ³J=8.6 Hz, ⁴J=5 Hz, ⁴J=1.93 Hz,1H)-7.35 (d ³J=8 Hz, 1H)-6.61 (s, 2H)-4.40-4.20 (broad, 1H)-3.92 (s,2H)-3.50-3.30 (broad, 1H)-3.30-3.20 (broad, 1H)-3.15-2.95 (broad,1H)-2.83 (d, ³J=20.7 Hz, 2H)-2.29 (s, 3H)-2.07-1.90 (broad,1H)-1.90-1.80 (broad, 1H)-1.83-1.77 (m, 1H)-1.75-1.60 (m, 1H).

EXAMPLE 4(3-Chloro-4-fluorophenyl)-4-fluoro-4-{[(5-methyl-6-methylaminopyridin-2-ylmethyl)amino]methyl}-piperidin-1-yl)methanone(Ib)

[1-(3-Chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl]-hydroxyacetonitrile(11.6 g, 0.037 mol), (6-methyl-amino-5-methylpyridin-2-yl)methylamine(6.8 g, 0.045 mol), 1,4-diazabicyclo[2.2.2]octane (9.1 g, 0.081 mol),sodium cyanoborohydride (3.8 g, 0.06 mol), FeSO₄.7H₂O (11.3 g, 0.0407mol) and 300 ml of methanol are introduced into a round-bottomed flask.The whole is stirred for 4 hours at room temperature and then evaporatedto dryness. The residue is taken up in water and extracted 3 times withethyl acetate, the organic phases are washed with water and then withsalt water and dried over MgSO₄. The evaporation of the solvent gives anoil which is then chromatographed on silica 60 with dichloromethane95-methanol 4.5-aqueous ammonia 0.5 to give 14.8 g of base (94%).Salification in ethyl acetate with one equivalent of glycolic acid givesa white crystalline salt.

m.p.=122° C. MS:ESI>O MH⁺ m/z=423. Elemental analysis:

calculated: C 55.37%-H, 5.86%-N, 11.23%. found: C, 55.17%; H, 5.99%; N,11.08%. ¹H NMR (D₂O): δ 7.61 (dd, ⁴J=2 Hz-⁴J=7 Hz, 1H)-7.47 (d ³J=7.1Hz, 1H)-7.45 (m, 1H)-7.39 (dd, ³J=8.6 Hz-³J=8.6 Hz, 1H)-6.73 (d, ³J=7.2Hz, 1H)-4.94 (s, HOD)-4.55-4.45 (d, ²J=11 Hz, 1H)-4.28 (s, 2H)-4.01 (s,2H)-3.70-3.80 (d, ²J=11 Hz, 1H)-3.45-3.60 (dd, ²J=11 Hz-³J=11 Hz,1H)-3.35-3.25 (m, 1H)-3.35 (d, ³J=20.5 Hz, 2H)-3.03 (s, 3H)-2.30-2.15(dd, ²J=10 Hz-³J=10 Hz, 1H)-2.17 (s, 3H)-2.10-1.90 (m, 1H)-1.95-1.80 (m,1H)-1.80-1.70 (m, 1H).

1. A method for preparing pyridin-2-yl-methylamine derivatives offormula (I):

in which: u represents a hydrogen atom or a methyl radical; v representsa hydrogen atom or a chlorine atom or a methyl radical; w represents ahydrogen atom or a fluorine atom or a methyl radical; y represents achlorine atom or a methyl radical; z represents a hydrogen atom or afluorine atom or a chlorine atom or a methyl radical; and A represents:a hydrogen atom or a fluorine atom or a chlorine atom; a C₁–C₅ alkylradical; a fluoroalkyl radical; a cyclopropyl radical; a 5-memberedaromatic heterocyclic group; an alkoxy or alkylthio group; a cyclicamino group; an alkoxycarbonyl group; or an amino group of the type:

 in which R2 or R3, which are identical or different, representhydrogen, or a C₁–C₅ alkyl radical as defined above or a cyclopropyl orcyclobutyl radical or a trifluoromethyl radical, comprising reacting acyanohydrin of formula (III):

 with a pyridin-2-ylmethylamines of formula (IV):

 in which the radicals u, v, w, y, z and A have the meanings given abovewith respect to formula (I).
 2. The method as claimed in claim 1,wherein the reaction is conducted in a reaction medium to which a simpleor complex boron hydride is added to make the reaction medium reducing.3. The method as claimed in claim 2, wherein the hydride is sodiumcyanoborohydride.
 4. The method as claimed in claim 1, wherein thereaction is conducted in the presence of a metal salt of iron, copper orzinc as a scavenger of cyanide ions.
 5. The method as claimed in claim4, wherein the metal salt is iron(II) sulfate, FeSO₄.7H₂O.
 6. The methodas claimed in claim 1, wherein the compound of formula (IV) is(5-methylpyridin-2-yl)methylamine of formula:


7. The method as claimed in claim 1, wherein the compound of formula(IV) is (6-methylamino-5-methylpyridin-2-yl)methylamine of formula:


8. A method for preparing (6-methylamino-5-methylamino-2-yl)methylamineof formula (IVb), comprising converting2-ethoxycarbonyl-5-methyl-6-pyridine of formula (IX) to2-carboxamido-5-methy-6chloropyridine of formula (X) by means of aqueousammonia:

treating compound (X) with methylamine in solution and in the presenceof CuSO₄ at high temperature and pressure to obtain2-methylamido-5-methyl-6-methylaminopyridine of formula (XI):

subjecting compound (XI) to acid hydrolysis to form5-methyl-6-methylaminopyridine-2-carboxylic acid of formula (XII):

converting compound (XII) to2-carboxamido-5-methyl-6-methyllaminopyridine of formula (XIII):

and, reducing compound (XIII) with lithium aluminum hydride to give(6-methylamino-5-pyridin-2-yl)methylamine of formula (IVb):


9. A method for preparing a(1-benzoyl-4-fluoropiperidin-4-yl)hydroxyacetonitriles of formula (III),comprising reacting an acetonitrile halide with a1-benzoylpiperidin-4-one of formula II to give the correspondingcyanoepoxide of formula V:

and, opening the cyanoepoxide of formula (V) with a fluorinating agent:

where y represents a chlorine atom or a methyl radical and z representsa hydrogen atom, a fluorine atom, a chlorine atom or a methyl radical.10. The method as claimed in claim 9, wherein the acetonitrile halide ischloroacetonitrile and the fluorinating agent is a hydrogenfluoride-pyridine complex.
 11. A synthesis intermediate of formula(III):

where y represents a chlorine atom or a methyl radical and z representsa hydrogen atom, a fluorine atom, a chlorine atom or a methyl radical.